Prevalence of Drug-resistant Klebsiella pneumoniae in Iran: A Review Article.

Background
The infections caused by drug resistant strains of Klebsiella pneumoniae are becoming an important health problem worldwide. There are several reports on antimicrobial resistant status of K. pneumoniae in Iran. However, a comprehensive analysis on drug-resistant K. pneumoniae from different parts of Iran has not yet been performed.


Methods
The searches were done according to several English and Persian databases including PubMed, Scopus, Iranmedex, and SID to identify studies addressing antibiotic resistant K. pneumoniae in Iran from Jan 1998 to Nov 2014. Comprehensive Meta-Analysis (V2.2, Biostat) software was used to analyze the data.


Results
The incidence rate of imipenem and ceftazidime resistance in K. pneumoniae isolates was 3.2% (95% confidence interval [CI], 1.5-6.5) and 55.7% (95% CI, 46.9-64.1), respectively. The highest rate of resistance in isolates of K. pneumoniae was seen against ampicillin (82.2%), aztreonam (55.4%) and nitrofurantoin (54.5%).


Conclusion
There is a relatively high prevalence of drug resistant K. pneumoniae isolates in Iran. Thus, a high degree of awareness among physicians and microbiologists, active infection control committee, appropriate antimicrobial therapy, improvement of hygiene condition and monitoring of drug resistant isolates are urgently needed in order to better control the emergence and spread of drug-resistant K. pneumoniae isolates in hospital settings.


Introduction
Klebsiella pneumoniae is an important causative agent of hospital-acquired infections, including severe pneumonia, urinary tract infection as well as septicemia and wound infections (1,2). This bacterium can survive in hospitals, persist on environmental surface and colonize different parts of human body. Therefore, transmission of this opportunistic pathogen can easily occur among patients via the hands of healthcare per-sonnel. Furthermore, the increased use of antibiotics and persistent exposure of K. pneumoniae to a number of antimicrobial agents, facilitating the emergence of multidrug-resistant strains, which has further intensified the infection control strategies in many health care settings (3). The most important resistant isolates of K. pneumoniae are carbapenem and cephalosporin resistant strains (4). These strains can cause seri-ous infections in immunocompromised patients, in association with prolonged hospital, stays, limited therapeutic options and increased mortality rates, ranging from 12% to as high as 72%, depending on the study population (5)(6)(7)(8)(9). In these regards, a reliable estimate of the extent of drug resistant isolates of K. pneumoniae is needed for the programmatic management of drug resistant strains within the context of national infection control programs. This study was designed to determine the prevalence of drug resistant strains of K. pneumoniae in Iran according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (10,11).

Search strategies
We conducted the search using PubMed, Web of Science, Cochrane library and Scopus for all studies addressing the prevalence of drug resistant strains of K. pneumoniae in Iran, from Jan 1998 to Nov 2014. The applied keywords include Klebsiella, Klebsiella pneumoniae, antibiotic resistance, antibiotic susceptibility, and Iran. Iranian databases including Iranmedex and Scientific Information Database (SID) were also searched (with Persian keywords).

Inclusion and exclusion criteria
We considered all the original articles about the incidence rate of drug resistant strains of K. pneumoniae from hospital-acquired infections in Iran. These articles should reference to the standard method, which recommended by clinical and laboratory standards Institute (CLSI) for drug susceptibility testing of K. pneumoniae against; carbapenems, cephalosporins and the other most used antimicrobial agents. Due to the following reasons, some studies were excluded from our analysis. Articles have focused only on community acquired K. pneumoniae or focused only on non-K. pneuomoniae stains, and studies not used CLSI recommended drug susceptibility testing methods. Furthermore, case reports, meta-analyses or systematic reviews, letters to editor, review articles, non-English or Persian studies, and duplicate publication, were also excluded.

Data extraction and definitions
The extracted data in current study include the first author's name, the publication time, year of study, number of samples, and prevalence of drug resistant strains of K. pneumoniae. Two authors extracted data from all of the included studies independently and a third investigator reviewed results.

Statistical analysis
The comprehensive meta-analysis software (ver. 2.0) was used to analyse the data. Because of the heterogeneity between studies, random effects models were used and tested with the Cochrane Q test. Moreover, Egger weighted regression and Begg rank correlation tests were performed to assess possible publication bias.

Results
Initially, 1353 articles were collected (Fig. 1). However, in a secondary screening, 1308 of them were excluded according to duplication, title, and abstract evaluation, and full-text of 45 papers was evaluated. Finally, 27 articles describing the prevalence of the ceftazidime-and/or imipenem-resistant strains of K. pneumoniae were selected for meta-analysis (Table 1). In all included studies, antimicrobial susceptibility testing had been performed using disc diffusion method as recommended by CLSI guidelines. Most of the studies were done in Tehran (n=11) compared with Isfahan (n=4), Fars (n=3), East Azerbaijan (n=2), Semnan (n=2), Hamadan (n=2), K. Boyer Ahmad (n=1), West Azerbaijan (n=1) and Kerman (n=1). Fig. 2 shows the distribution of drugresistant strains of K. pneumoniae in different regions of Iran. The prevalence of imipenem and ceftazidime resistance was found to be 3.2% (95% CI, 1.5-6.5) and 55.7% (95% CI, 46.9-64.1), respectively ( Table 2). Fig. 3 and 4 show the forest plot of the Meta-analysis of imipenem and ceftazidime resistant K. pneumoniae.   Some evidence for publication bias for imipenem and ceftazidime was observed (P<0.05 for Begg rank correlation analysis; P<0.05 for Egger weighted regression analysis) (Fig. 5, 6). The resistance of K. pneumoniae to other important antimicrobial agents is shown in Table 3.

Discussion
The emergence and spread of carbapenem and cephalosporin resistant strains of K. pneumoniae are a considerable threat to public health (2). The major goal of this systematic review was to evaluate the current situation and distribution of drugresistant K. pneumoniae in Iran. This analysis showed that 3.2% K. pneumoniae isolates from Iran was resistant to imipenem and 55.7% to ceftazidime. Thereby despite ceftazidime, the imipenem remains as a powerful weapon against K. pneumoniae isolates in Iran. In the current study more than half of K. pneumoniae isolates were resistant to other important antimicrobial agents such as aztreonam (55.4 %), nitrofurantoin (54.5%) and co-trimoxazole (51.8%), we highly recommend that antimicrobial test should be performed prior to any antibiotic prescription in K. pneumonia infections. Very low number of K. pneumonia population (17.8%) were sensitive to ampicillin suggesting ampicillin is not effective drug for empiric treatment of K. pneumonia infections unless we use it in combination with other relevant drugs. The relatively high rates of drug resistant isolates of K. pneumoniae observed in this study may have several negative effects on public health issues (39). For example, this could cause difficulty in treating K. pneumoniae associated infections since fewer effective drugs are available for treating those highly drug-resistant strains. Unfortunately, these microorganisms are even showing rising rates of resistance to new expensive antibiotics subsequently considered the treatment of choice (40). This is due to the widespread use of broadspectrum antibiotics in health care settings for empiric treatment of infections. Furthermore, patients infected with these pathogens require prolonged antimicrobial therapy that has considerable implications for the individual patient and for the health care settings. Finally, infections due to these highly resistant strains are reported to be associated with higher morbidity and mortality rates (41). In Iran, 50000 people die each year because of multidrug-resistant bacterial infections and that this costs Iranian economy 2.5 million dollars annually (4). Some important reasons for the increasing rates of drug resistant isolates in Iran include limited infection surveillance programs, the lack of communication between physicians and microbiologists, lack of standardized or accepted criteria to determine drug resistant isolates, limited laboratory facilities, and poor sanitation. Therefore, active infection control committee, appropriate antimicrobial therapy, and improvement of hygiene condition will prevent or lower the emergence of antimicrobial-resistant pathogens (42). Current review was carried out according to provinces of Iran and the published time. Because of many hospitals and health care centers in Tehran Province, Iran, patients from other provinces come to Tehran for better treatment. Therefore, most of the studies in this analysis belonged to Tehran, where the ceftazidimeand/or imipenem-resistant strains of K. pneumoniae mostly reported by researchers.

Conclusion
There is a relatively high prevalence of drug resistant K. pneumoniae isolates in Iran. Thus, a high degree of awareness among physicians and microbiologists, active infection control committee, appropriate antimicrobial therapy, improvement of hygiene condition and monitoring of drug resistant isolates are urgently needed in order to better control the emergence and spread of drugresistant K. pneumoniae isolates in hospital settings.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.

Conflict of Interests
The authors declare that there is no conflict of interests.